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bioRxiv · 10.1101/153403

Structure of the human pro-myostatin precursor and determinants of growth factor latency

Cotton, T. R.·Fischer, G.·Wang, X.·McCoy, J. C.·Czepnik, M.·Thompson, T. B.·Hyvonen, M.
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Abstract

Myostatin, a key regulator of muscle mass in vertebrates, is biosynthesised as a latent precursor in muscle and is activated by sequential proteolysis of the pro-domain. To investigate the molecular mechanism by which pro-myostatin remains latent, we have solved the structure of unprocessed promyostatin and analysed the properties of the protein in its different forms. Crystal structures and SAXS analyses show that pro-myostatin adopts an open, V-shaped structure with a domain-swapped arrangement. The pro-mature complex, after cleavage of the furin site, has significantly reduced activity compared with mature growth factor and persists as a stable complex that is resistant to the natural antagonist follistatin. The latency appears to be conferred by a number of distinct features that collectively stabilise the interaction of the pro-domains with the mature growth factor, enabling a regulated step-wise activation process, distinct from the prototypical pro-TGF-{beta}1. These results provide a basis for understanding the effect of missense mutations in pro-myostatin and pave the way for the design of novel myostatin inhibitors.

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Cotton, T. R., Fischer, G., Wang, X., McCoy, J. C., Czepnik, M., Thompson, T. B., Hyvonen, M.. 2017-06-23. Structure of the human pro-myostatin precursor and determinants of growth factor latency. https://doi.org/10.1101/153403

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